Aryl aryl methyl thio arenes prevent multi-drug resistant malaria in mouse by promoting oxidative stress in parasite

Abstract

A series of aryl aryl methyl thio arenes (AAMTAs) have been synthesized through Grignard reaction of arylmagnesium bromide with various carbaldehydes followed by Friedel Crafts alkylation of diaryl carbinols with heteroaryl thiols and evaluated their antimalarial efficacy. These compounds displayed potent antimalarial activity in vitro against human malaria parasite Plasmodium falciparum (P. falciparum) and in vivo against multi-drug resistant Plasmodium yoelii in mouse model. AAMTAs dose-dependently induce reactive oxygen species (ROS) generation, which oxidize proteins and lipids in parasite and develop oxidative stress. Furthermore, AAMTAs treatment depletes the level of GSH, which is essential for antioxidant defense and survival during intra-erythrocytic stages of P. falciparum. The data also document that AAMTAs inhibit hemozoin formation, which may contribute to AAMTAs-mediated oxidative stress as a result of pro-oxidant free heme accumulation. AAMTAs containing 3-pyridyl ring were found to be more efficient to offer antimalarial activity. Efforts have been given to synthesize achiral AAMTAs 17-23 and among them, compound 18 showed most promising antimalarial activity in vivo against MDR strain (Plasmodium yoelii) using Balb/c mouse model.